Phenacylsulfonyl pyridine compounds



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PHENACYLSULFONYL PYRIDINE COMPOUNDS Moses Wolf Goldberg, Upper Montclair, and Sidney Teitel, Nutley, N. J., assignors to Hotfmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application July 7, 1954, Serial No. 441,950

8 Claims. (Cl. 260294.8)

S OPC-C Oaryl N R wherein R is a member of the group consisting of hydrogen and lower alkyl, and salts thereof. The aryl in the above formula refers to monocyclic aryl groups including phenyl and nuclearly substituted phenyl, such as halophenyl, hydroxyphenyl, alkoxyphenyl, acyloxyphenyl, cyanophenyl, nitrophenyl, aminophenyl, etc. The ring substituents of the alkoxyphenyl and acyloxyphenyl groups are preferably lower alkyl derivatives such as methoxyphenyl and acetoxyphenyl groups.

Salts of the novel compounds, such as the acid addition salts and quaternary salts, are particularly within the scope of this invention. These salts include acid addition salts, such as the hydrohalides, e. g. hydrochlorides, sulfates and toluenesulfonates, and quaternary salts, such as the lower alkyl halide, aryl halide and aralkyl halide quaternary salts.

The novel compounds of this invention are produced by reacting an alkali metal salt of 3-pyridinesulfinic acid with a phenacyl halide in an organic solvent such as ethanol, dimethylformamide, acetone, nitromethane, etc. The free base thus obtained may be converted into the acid addition salt by reacting the base in a solventwith a strong. acid, such as a mineral acid. Quaternary salts are produced by reacting the free base in an organic solvent suchv as nitromethane, acetone, acetonitrile, ethanol, etc. with a quaternizing agent, such as analkyl halide, an aralkyl halide, a phenacyl halide, etc.

3-pyridinesulfinic acid, which is a starting material for the compounds of this invention, is prepared by condens: ing 3-pyridinesulfonyl chloride with hydrazine to produce S-pyridinesulfonic acid hydrazine and reacting the latter with acetone. By neutralizing an aqueous solution of 3- pyridinesulfinic acid with sodium hydroxide and evaporating the resulting solution, the sodium salt of'3-pyridinesulfinic acid is obtained.

The aminophenacyl sulfones of this class can be obtained, for example, by deacetylating the corresponding acetamidophenacyl sulfcnes with a strong aqueousacid. The hydroxyphenacyl sulfones are similarly. obtained from the corresponding acetoxyphenacyl sulfones.

The compounds ofv this invention areusefulas anthelmintics; for example, they are active against worms of the family oxyuridae.

Example 1 19.9 grams (0.12 mol) of the dry sodium salt of 3- pyridinesulfinic acid and 18.6 grams (0.12 mol) of'phenacyl chloride, dissolved in 200 mli of absolute? ethanol, were refluxed for 15 hours. The mixturewas'then cooled;

The reaction product was filtered oil and extracted in a Soxhlet apparatus with methanol. The methanol extract was concentrated to a small volume, cooled, and the crystals which had formed were filtered off and dried. The phenacyl 3-pyridyl sulfone was recrystallized from benzene and melted at 106-107 C.

Calculated for C13H11NO3S: C, 59.76; H, 4.24. Found: C, 59.80; H, 4.35.

Example 2 9.1 grams (0.035 mol) of phenacyl 3-pyridyl sulfone were dissolved in 200 ml. of ice cold acetone containing 40% methyl bromide by Weight. The solution, in a tightly stoppered flask, was allowed to warm slowly to room temperature and then was stored overnight. The crystals which had formed were filtered 01f,- washed with acetone and dried. The 1-methyl-3-phenacylsulfonylpyridinium bromide, upon recrystallization from acetonitrile-acetone-ether, melted at 124-127 C.

Calculated for C14H14BrNO3S: C, 47.22; H, 3.96. Found: C, 47.46; H, 4.30.

Example 3 To 12 grams (0.046 mol) of phenacyl 3-pyridyl sulfone dissolved in ml. of nitromethane were added 25 grams (0.23 mol) of ethyl bromide. The solution was heated in a sealed tube at 65 for 16 hours and then cooled. The volatiles were distilled ofi. The residue was crystallized from ethanol-ether. The lethyl-3-phenacylsulfonylpyridinium bromide melted at l63'-l64 C. with decomposition.

Calculated for C15H16BINO3S: C, 48.66; H, 4.36. Found: C, 48.30; H, 4.37.

Example 4 To a suspension of 12 grams (0.046 mol) of phenacyl 3-pyridyl sulfone in 75 ml. of nitromethane were added 13.7 ml. (0.15 mol) of n-propyl bromide. pension was heated in a sealed tube at 65 C. for 15 hours. The resulting solution was cooled and the volatileswere distilled ofi. The residual solid, l-propyl-3-phenacylsulfonylpyridinium bromide was recrystallized from ethanol-ether, M. P. 181-182" C. with decomposition;

Calculated for CIGHIBBINOBSI C, 50.01; H, 4.72. Found: C, 49.99; H, 4.88.

Example 5 Example 6 To a suspension of 12 grams (0.046 mol) of phenacyl 3-pyridyl sulfone in 75 ml. of nitromethane were added 16': ml. of n-amyl bromide. The suspension was heated in. a sealed'tube at 65 for 15 hours. The resulting solution was cooled and the volatiles were then distilled off. The residual solid was recrystallized from ethanol-methyl ethyl ketoneeether. The l-amyl-3-phenacylsulfonylpyridiniumbromide melted at -l22 'C.

Calculated for C18H22BI'NO3S: C, 52.43; H, 5.38. Found: C, 52.71; H, 5.14.

Example 7 10.2grams (0.038 mol) of phenacyl 3-pyridyl 'sulfone were dissolved in ml. of acetonitrile. To the solution The suswere added 8.3 grams (0.038 mol) of p-uitrobenzyl bromide. The mixture was stirred and refluxed for 8 hours and cooled. The crystals were filtered off, washed with acetonitrile and dried. The p-nitrobeuzyl bromide of phenacyl 3-pyridyl sulfone hemihydrate was recrystallized from water-acetonitrile-etl'ier, M. P. 178180 C. with decomposition.

Calculated for C20H17B1N205S.1/2H202 C, 49.40; H, 3.73. Found: C, 49.72; H, 3.75.

Example 8 To a suspension of 17 grams (0.065 mol) of phenacyl 3-pyridyl sulfone in 75 ml. of nitromethane were added 12 grams (0.078 mol) of phenacyl chloride. Thesuspension was heated in a sealed tube at 65 C. for 16 hours. The resulting solution was cooled and the volatiles were distilled off. 'The residual solid was recrystallized from ethanol-ether and the 1-phenacyl-3-phenacylsulfonylpyridinium chloride melted at 195-197 C. with decomposition.

Calculated for CzrHmClNOrS: C, 60.66; H, 4.36. Found: C, 60.60; H, 452.

Example 9 To a well stirred suspension of 28.6 grams (0.2 mol) of 3-pyridinesulfinic acid in 250 ml. of absolute ethanol were added 12 grams of sodium methoxide (85%). To the resulting neutral solution were added 42.6 grams (0.2 mol) of a-bromopropiophenone. After minutes of refluxing, the solution became turbid. The mixture was stirred and refluxed for 15 hours, then filtered while hot. The filtrate was concentrated in vacuo to remove the vol-atiles. The residual gum was washed with water and then crystallized from ethanol-isopropanol. The a-rnethylphenacyl 3-pyridyl sulfone melted at 8182 C.

Calculated for C14H13NO3S: C, 61.08; H, 4.76. Found: C, 61.36; H, 4.62.

Example Example 1 1 18 grams (0.12 mol) of 3-pyridinesulfinic acid were reacted with 33 grams (0.12 mol) of p-bromophenacyl bromide according to the procedure described in Example 9. The p-bromophenacyl 3-pyn'dyl sulforre, recrystallized from dimethylformamide-water, melted at 146-148" C. with decomposition.

Calculated for CmI-ImBrNOsS: C, 45.88; H, 2.96. Found: C, 45.80; H, 2.88.

Example 12 50 ml. of acetone, containing 40% methyl brornide by weight, were added to 10.2 grams (0.03 mol) of p-bromophenacyl 3-pyridyl sulfone dissolved in 50 ml. of dimethylformarnide. The solution was stored in a tightly stoppered flask at room temperature for 72 hours. The volatiles were distilled off and the residue was crystallized from 95% ethanol. The 1-methy13-(p-bromophenacyl sulfonyDpyridinium bromide melted at 133- 134 C. with decomposition.

Calculated for CmHisBrzNOasz C, 38.64; H, 3.01. Found: C, 38.68; H, 3.19.

Example 13 To 2.98 grams (0.13 mol) of sodium, dissolved in 200 ml. of absolute ethanol, were added 18.7 grams (0.13 mol) of 3-pyridinesulfinic acid and 24 grams (0.13 mol) of p-methoxyphenacyl chloride. The mixture was stirred and refluxed for 15 hours, filtered while hot, and the crystalline residue was washed thoroughly with water and air dried. The p-methoxyphenacyl 3-pyridyl sulfone thus obtained melted at 106-108" C.

An ice cold suspension of 20.6 grams of the product obtained in the preceding paragraph was treated with 200 ml. of acetone, containing 40% methyl bromide by weight. The mixture was heated in a sealed tube at for 8 hours and then cooled. The crystals obtained were filtered off, washed with acetone and dried. The 1-methy1-3- (p-methoxyphenacylsulfonyl)pyridinium bromide, upon recrystallization from methanol-ether, melted at 183- 185 C.

Calculated for C1sH1sBrNO4S: C, 46.63; H, 4.18. Found: C, 46.69; H, 4.49.

Example 14 p-Acetoxyphenacyl bromide was prepared by slowly adding 22 grams of bromine to a solution of 24.7 grams of p-acetoxyacetophenone in 100 ml. of absolute ether containing 0.2 gram of anhydrous aluminum chloride. The volatiles were then distilled off in vacuo and the residue triturated with water and petroleum ether. The product was then filtered oil and crystallized from etherpetroleum ether, M. P. 6567 C.

11.5 grams (0.08 mol) of 3-pyridinesulfinic acid and 20 grams (0.078 mol) of p-acetoxyphenacyl bromide were reacted according to the procedure described in Example 9. The reaction product, p-acetoxyphenacyl 3-pyridyl sulfonc, was recrystallized from acetone-ether, M. P. 128- 129 C.

Calculated for C15H13NO5S: C, 56.41;

Found: C, 56.34; H, 4.07.

1 methyl 3 (p-acetoxyphenacylsulfonyl)pyiidiniuin bromide, M. P. 78-80" C., was prepared by the procedure described in Example 10 from 14 grams (0.044 mol) of p-acetoxyphenacyl 3-pyridyl sulfone and methyl bromide. The product was recrystallized from acetonitrileethyl acetate.

Calculated for CmHmBrNOsS: C, 46.39; H, 3.89. Found: C, 46.64; H, 4.12.

Example 15 To 17 grams (0.036 mol) of 1-methyl-3-(p-acetoxyphenacylsulfonyl)pyridinium bromide, dissolved in 100 'ml. of water, were added 15 ml. of 48% hydrobromic Example 16 p-Cyanophenacyl bromide was prepared by slowly adding 34 grams of bromine to a solution of 34 grams of p-cyanoacetophenone in 100 ml. of absolute ether containing 0.3 gram of anhydrous aluminum chloride. The volatiles were then distilled all in vacuo, the residue triturated with water and crystallized from ethanol, M. P. 90-92 C. V

28.6 grams (0.2 mol) of 3-pyridinesulfinic acid and 44.8 grams (0.2 mol) of p-cyanophenacyl bromide were reacted according to the procedure described in Example 9. The reaction product, p-cyanophenacyl 3-pyridyl sultone was recrystallized from 60% ethanol, M. P. 169- 170 C.

7 Calculated for CmHmNzOaS: C, 58.73; H, 3.52. Found: C, 58.56; H, 3.82.

By proceeding in the manner described in Example 10, l-methyl 3 (p-cyanophenacylsulfonyl)pyridinium bromide, M. P. 206207 C. with decomposition, was prc pared by reacting 13 grams (0.045 mol) of p-cyanophenacyl 3-pyridyl sulfone with methyl bromide. The product was recrystallized from water-ethanol.

Calculated for C15Hi3BrN2OsS: C, 47.25; H, 3.44. Found: C, 47.47; H, 3.71.

Example 1 7 14.3 grams (0.1 mol) of 3-pyridinesulfinic acid and 24.4 grams (0.1 mol) of p-nitrophenacyl bromide were reacted according to the procedure described in the first paragraph of Example 13 to produce p-nitrophenacyl 3- pyridyl sulfone, M. P. 144-146 C. The product was recrystallized from acetonitrile-ethanol.

Calculated for CraHmNzOsS: C, 50.98; H, 3.29. Found C, 51.33; H, 3.58.

To a suspension of 9.2 grams (0.03) of p-nitrophenacyl 3-pyridyl sulfone in 100 ml. of acetonitrile were added 100 ml. of acetone containing 40% methyl bromide by weight. The mixture was heated in a sealed tube at 100 C. for 8 hours. The mixture was cooled, the crystals were filtered 01f, washed with acetone and dried. The 1- methyl-3-(p-nitrophenacylsulfonyl)pyridinium bromide, recrystallized from 80% ethanol, melted at 195-196 C. with decomposition.

Calculated for Cul-IraBrNzOaS: C, 41.92; H, 3.27. Found: C, 41.89; H, 3.19.

Example 18 28.6 grams (0.2 mol) of 3 pyridinesulfinie acid were reacted with 42.4 grams (0.2 mol) of p-acetamido-achloroacetophenone according to the procedure described in the second paragraph of Example 14. The pacetamidophenacyl 3-pyridyl sulfone, upon recrystallization from 60% ethanol, melted at 196l97 C. with decomposition.

By reacting 24.8 grams (0.078 mol) of p-acetamidophenacyl S-pyridyl sulfone and methyl bromide in dimeth ylformam'ide according to the procedure described in Ex ample 12, 1-methy1-3-(p-acetamidophenacylsulfonyl)pyridinium bromide, M. P. 209-210 C. with decomposition, was obtained. The product Was recrystallized from water-methanol-acetone.

Calculated for C1sH17BrN2O4S: C, 46.49; H, 4.15. Found: C, 46.34; H, 4.34.

1-methyl-3-(p-aminophenacylsulfonyl)pyridinium bromide hydrobromide, M. P. above 330 C., Was prepared by deacetylating 15 grams (0.036 mol) of 1-methyl-3- (p-acetamidophenacylsulfonyl)pyridinium bromide with 15 m1. of 48% hydrobromic acid according to the procedure described in Example 15. The product was recrystallized from water-methanol-acetonitrile.

Calculated for C14H1sBrN2O3S.HBr: C, 37.19; H, 3.57. Found: C, 37.25; H, 3.95.

We claim:

1. A compound selected from the group consisting of bases having the formula wherein R represents a member of the group consisting of hydrogen and lower alkyl, and aryl represents a member of the group consisting of phenyl, bromophenyl, hydroxyphenyl, lower-alkoxyphenyl, lower-alkanoic acid acyloxyphenyl, cyanophenyl, nitrophenyl and aminophenyl, and phannaceutically acceptable acid addition salts and quaternary salts of said bases.

2. Phenacyl 3-pyridyl sulfone.

3. Pharmaceutically acceptable quaternary salts of a compound according to claim 2.

4. p-Acetoxyphenacyl 3-pyridy1 sulfone.

5. Pharmaceutically acceptable quaternary salts of a compound according to claim 4.

6. 1-butyl-3-phenacylsulfonylpyridinium bromide.

7. 1-amyl-3-phenacylsulfonylpyridinium bromide.

8. 1-methyl-3- (p-acetoxyphenacy1su1fonyl)pyridinium bromide.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES HAVING THE FORMULA 